Give me A5 for lipoprotein hydrolysis!
Martin Merkel, Joerg Heeren
Martin Merkel, Joerg Heeren
Published October 3, 2005
Citation Information: J Clin Invest. 2005;115(10):2694-2696. https://doi.org/10.1172/JCI26712.
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Commentary

Give me A5 for lipoprotein hydrolysis!

Abstract

APOA5 is a newly identified apolipoprotein that plays a crucial role in the regulation of plasma triglyceride levels. In several human studies, common APOA5 single nucleotide polymorphisms have been strongly associated with elevated plasma triglyceride levels. In this issue of the JCI, Marçais et al. report that the rare Q139X mutation in APOA5 leads to severe hypertriglyceridemia by exerting a dominant-negative effect on the plasma lipolytic system for triglyceride-rich lipoproteins. The presented data support the idea that the molecular mechanism of APOA5 function may include the enhancement of binding between lipoproteins and proteoglycans at the vascular wall and activation of proteoglycan-bound lipoprotein lipase.

Authors

Martin Merkel, Joerg Heeren

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Figure 1

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Triglyceride-lowering effect of APOA5. (A) Triglyceride-rich lipoprotein...
Triglyceride-lowering effect of APOA5. (A) Triglyceride-rich lipoproteins such as VLDL are hydrolyzed by the lipolytic action of dimeric LPL, which is bound to heparan sulfate proteoglycans on the vascular endothelium. We propose that APOA5 targets VLDL to proteoglycans, placing VLDL in close proximity to LPL. At the same time, APOA5 may activate proteoglycan-bound LPL by stabilizing the dimerized conformation or by binding to an LPL allosteric site. After hydrolysis, remnant particles (Rem) are released into the circulation, and APOA5 can be transferred and reused by other VLDL particles. In the postprandial situation, HDL can act as an APOA5 donor for intestinally derived chylomicrons. Thus, APOA5 is a potent activator of the natural lipolytic system. (B) Proposed situation in patients with the Q139X mutation in APOA5 (Q139X-APOA5). Truncated APOA5 is not associated with lipoproteins and cannot sufficiently target triglyceride-rich lipoproteins to proteoglycans. Instead, binding of the Q139X mutation in APOA5 to proteoglycan-bound LPL results in detachment and degradation of LPL.